Principal Investigator/Program Director (Last, First, Middle: Chen, Ridong Abstract Interleukin-2 (IL-2) immunotherapy can result in remarkable long-term responses in some cancer patients by stimulating the immune response to kill tumor cells. However, current rIL-2 therapy is limited to highly selected patients due to its requirements for high and frequent dosing, which can result in severe side effects. Moreover, rIL-2 also activates CD4+ regulatory T cells, which suppress the immune response. To ameliorate the liabilities of the current rIL-2 drug, we have designed a long-acting IL-2 analog that selectively preserves immune response activation (CD8+ T, NK cells), without activating regulatory T cells and endothelial cells; thereby, minimizing immune suppression and vascular leak syndrome. We propose to optimize combination of rIL2 analog treatment plus antitumor antibody to safely and effectively kill tumor cells via a concerted innate and adaptive response involving neutrophils, NK cells, macrophages, and CD8+ T cells. In this study, the Specific Aim is to use the syngeneic mouse model of B16-F10 to determine whether the combination of the proprietary IL-2 analog with an antitumor antigen antibody effectively eradicates established tumors without inducing adverse side effects. Our long-term goal is to develop the proprietary IL-2 analog as a safe immunotherapy to cure cancer or extend survival of patients.